One approach to cancer therapy has been the use of differentiation to arrest the growth of tumor cells. In order to apply differentiation therapy to cancer treatment, a mechanistic understanding of differentiation in tumor cells must be attained including which factors, genetic or otherwise, abrogate or enhance the effects of the differentiation agent. Vitamin A compounds (retinoids) are modulators of epithelial cell proliferation and differentiation. Retinoids have been used successfully to prevent epithelial tumors. The initiation of retinoid regulated differentiation requires changes in gene expression mediated by a cascade of transcriptionally regulated proteins. These factors may include the retinoic acid receptors and classical transcription factors such as homeobox genes. Our goal for this study is to understand the mechanism of retinoid responsiveness by studying retinoid modulated expression of genes in a human squamous cell carcinoma of the oral cavity for which we have isolated cDNA clones. We will investigate how transcription factors participate in their regulation and whether the activation of oncogene(s) plays a role in the progression of cells to a differentiation resistant state. We will analyze how oncogenes affect expression of differentiation regulated genes and whether alterations in transcription factors influence the oncogene effects on retinoid responsiveness of human epithelial cells from the oral cavity. We seek to identify critical genetic changes in human head and neck cancers and study how they affect growth, differentiation and differentiation regulated gene expression in human squamous cell carcinoma cell lines from the head and neck. These genetic elements include oncogenes, growth factors and growth factor receptors. We will try to identify changes in these genes such as overexpression and amplification in squamous cell carcinoma cell lines which may alter their response to retinoid-based differentiation therapy. Utilizing cDNA clones of retinoic acid responsive genes which we have isolated, we will study the mechanism of their modulation in epithelial cells and epithelial cancer cell lines of the head and neck to see if they are regulated similarly before and after tumorigenic transformation.